Cardiovascular disease (CVD) is an emerging problem in human immunodeficiency virus (HIV)-1-infected adults, including those treated with antiretroviral therapy (ART). Prospective and retrospective studies have indicated that HIV-1-infected individuals on ART are at increased risk of atherosclerosis and myocardial infarction compared with HIV-1-seronegative individuals. Much of the risk associated with accelerated atherosclerosis in the HIV-1-infected population is independent of traditional risk factors, and the mechanisms underlying this are not completely understood. Furthermore, effective non-pharmacological intervention strategies to prevent and/or reduce the risk of atherosclerotic vascular disease in HIV-1-infected adults receiving ART have not been established. There is increasing evidence that ART-treated HIV-1-infected individuals have a proatherogenic endothelial phenotype characterized by impaired vasomotor and fibrinolytic regulation. Regular aerobic exercise is widely regarded as the most effective non-pharmacological intervention for both primary and secondary prevention of CVD. To date, studies on the effects of aerobic exercise training in HIV-1-seropositive adults have focused on cardiorespiratory and metabolic adaptations. It is currently unknown whether aerobic exercise training can improve endothelial function in HIV-1-infected adults receiving ART. Accordingly, specific aims 1 and 2 of the present proposal will be to determine if a program of regular aerobic exercise improves: 1) vascular endothelium-dependent nitric oxide-mediated vasodilation;and 2) the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA) in previously sedentary HIV-1-infected adults without traditional cardiometabolic risk factors for coronary artery disease who are receiving antiretroviral therapy. Specific aim 3 will determine if the exercise-induced increase in endothelial vasodilator and fibrinolytic function in HIV-1-infected adults receiving antiretroviral therapy is due, at least in part, to reduced oxidative stress and inflammation. To address these aims, 80 HIV-1-seropositive adults, ranging in age from 30-50 years, receiving their first ART regimen consisting of tenofovir and emtricitabine combined with either efavirenz or atazanavir boosted with ritonavir will be studied. Subjects will be randomly assigned to either an aerobic exercise training group or an attention control group for 24 weeks. Endothelium- dependent vasodilation, endothelial t-PA release and the effects of oxidative stress on each functional characteristic will be determined before and after the 24-week intervention period using an isolated forearm model. The results of the present study will provide mechanistic insight into the accelerated atherosclerosis seen in HIV-1-infected individuals and support use of regular aerobic exercise as adjunctive therapy to reduce and prevent cardiovascular disease in this highly susceptible population. PUBLIC HEALTH RELEVANCE: The general aim of this application is to determine the effects of regular aerobic exercise on vascular endothelial function in human immunodeficiency virus (HIV)-1-infected adults receiving antiretroviral therapy. Our general hypothesis is that regular aerobic exercise will reverse impairments in vascular endothelial vasodilator and fibrinolytic function in HIV-1-infected adults on ART through reductions in inflammation and oxidative stress. If this hypothesis is supported by the results of the proposed study, these data will provide mechanistic insight into the accelerated atherosclerosis seen in HIV-1-infected individuals and support the use of regular aerobic exercise to reduce and prevent cardiovascular disease in this highly susceptible population.